Mitochondria from many sources possess phospholipase A.sub.2 activity associated with both their inner and outer membranes. The physiological functions of this enzyme or enzyme group has not been established with certainty although several reasonable, potential functions can be hypothesized. These include the possible involvement of mitochondrial phospholipase A.sub.2 in regulating membrane permeability and therefore such processes as calcium ion (Ca.sup.+2) accumulation and release, the efficiency of ATP synthesis, and cellular thermogenesis. Other possible functions of this enzyme include the modification of phospholipid acyl group composition, the initiation phospholipid degradation, and the liberation arachidonic acid to initiate the "arachidonic acid cascade," which involves the synthesis of prostaglandins and related compounds. While generally the products of the cascade are beneficial, in certain disease processes and other conditions the production of prostaglandins and similar products induces deleterious consequences such as inflammation (see paper by N. A. Plummer et al., abstracted in Journal of Investigative Dermatology, Vol. 68, No. 4, p. 246 (1977)); erythema; platelet aggregation (B. B. Vargaftig, J. Pharm. Pharmacol., Vol. 29, p. 222-228 (1977)); and the release of SRS-A (slow reacting substance-anaphylaxis), a known mediator of allergic responses. The inhibition of phospholipase A.sub.2 can prevent these and similar conditions mediated by the action of this enzyme.
In cells which are injured by ischemia, chemical, mechanical or other means, the mitochondria develop impaired functional capacities and the extent of these metabolic lesions can be pivotal factors in the recovery or death of the injured cell. Persistent activation of mitochondrial phospholipase A.sub.2, arising because of loss of cellular Ca.sup.2+ homeostasis, is a probable dominant mechanism by which mitochondrial damage develops. There is also reason to suspect that phospholipase A.sub.2 -dependent loss of mitochondrial function may play an important role in the etiology of several significant human diseases including Reye's syndrome, muscle wasting diseases and malignant hyperthermia.
Thus a need exists for compounds which act to inhibit the activity of phospholipase A.sub.2. Useful inhibitory compounds would be specific, potent and nontoxic. The inhibitors could be employed to control mitochondrial damage and damage to other membranous structures in injured or diseased mammalian tissue and thereby limit permanent damage and improve cellular survival. Hereinafter the deleterious effects and pathologies dependent entirely or in part upon phospholipase A.sub.2 activity will be referred to as phospholipase A.sub.2 mediated conditions (PMC).